The Prognostic Impact of MYC Gene-Related Abnormalities on Multiple Myeloma Outcome through Fluorescence in situ Hybridization Analysis.

INTRODUCTION: Chromosomal abnormalities (CAs) have been identified as important factors in determining the biological features and prognostic value of multiple myeloma (MM). MYC gene-related abnormalities (MYC GAs) are one of the CAs, but their unfavorable impact has not been fully investigated in daily clinical practice. METHODS: This study retrospectively analyzed the prognostic impact of MYC GAs on 81 patients through fluorescence in situ hybridization analysis in our institute. RESULTS: MYC GAs were associated with poor overall survival (hazard ratio [HR], 3.08; 95% confidence interval [CI]: 1.23-7.73; p = 0.017), progression-free survival (PFS) (HR, 2.96; 95% CI: 1.58-5.53; p < 0.001), and time to next treatment (TNT) (HR, 2.11; 95% CI: 1.13-3.93; p = 0.018) in the median follow-up of 34.7 months. Furthermore, MYC GAs with an additional chromosome 8 (MYC-Ch8(+)) were associated with shorter PFS (HR, 3.15; 95% CI: 1.38-7.2; p = 0.0064), whereas MYC GAs without an additional chromosome 8 (MYC-Ch8(-)) were associated with shorter PFS (HR, 3.62; 95% CI: 1.51-8.68; p = 0.004) and shorter TNT (HR, 3.72; 95% CI: 1.41-9.81; p = 0.0078). CONCLUSION: These findings could help identify high-risk patients with MM. Further prospective studies are needed to confirm the significance of MYC GAs for the MM prognostic effect.

Increased SLAMF7high monocytes in myelofibrosis patients harboring JAK2V617F provide a therapeutic target of elotuzumab.

Monocyte-derived fibrocytes recently garnered attention because the novel pathogenesis of myelofibrosis (MF), and suppression of fibrocyte differentiation by serum amyloid P remarkably improved MF. We previously revealed that human fibrocytes highly expressed signaling lymphocytic activation molecule F7 (SLAMF7) compared with macrophages and that SLAMF7high monocytes in the peripheral blood (PB) of MF patients were significantly elevated relative to those in healthy controls (HCs). In this study, we evaluated SLAMF7high monocyte percentage in the PB of HCs, myeloproliferative neoplasm (MPN) patients with MF, and MPN patients without MF by using a cross-sectional approach. We found that MPN patients with MF who harbored JAK2V617F had a significantly elevated SLAMF7high monocyte percentage, which correlated positively with the JAK2V617F allele burden. In addition, the serum concentration of interleukin-1ra (IL-1ra) was significantly correlated with the SLAMF7high monocyte percentage and JAK2V617F allele burden. These findings suggest that both SLAMF7high monocytes and IL-1ra could be useful noninvasive markers of MF onset. Furthermore, the JAK2V617F allele burden of SLAMF7high monocytes was significantly higher than that of SLAMF7low monocytes and could be a potential target of elotuzumab (Elo), an anti-SLAMF7 antibody used for treating multiple myeloma. Elo independently inhibited differentiation of fibrocytes derived not only from HCs but also from MF patients in vitro. Elo also ameliorated MF and splenomegaly induced by romiplostim administration in humanized NOG mice. In conclusion, an increase of SLAMF7high monocytes with higher JAK2V617F allele burden was associated with the onset of MF in MPN patients harboring JAK2V617F, and Elo could be a therapeutic agent for MPN patients with MF who harbor JAK2V617F.

Enhanced Z-Isomerization of Astaxanthin in Paracoccus carotinifaciens via Microwave Drying.

The effects of microwave drying conditions of a Paracoccus carotinifaciens culture solution on astaxanthin Z-isomerization and degradation were investigated. The microwave drying significantly increase the ratio of astaxanthin Z-isomers, and the higher the microwave power and the longer the drying time, the higher the total Z-isomer ratio of astaxanthin, but such conditions also accelerated astaxanthin degradation. We found that the addition of powdered oils enhanced the Z-isomerization reaction. For example, when the P. carotinifaciens culture solution was dried at 1000 W power for 5 min without and with powdered rapeseed oil, total Z-isomer ratios of astaxanthin in resulting dried powder were 14.9 and 47.4%, respectively. Furthermore, the storage test of the dried P. carotinifaciens powder showed that astaxanthin Z- isomers were stable at 4℃ in a low-oxygen atmosphere. As astaxanthin Z-isomers have greater bioavailability and potentially exhibit superior biological activities than the all-E-isomer, the dried P. carotinifaciens powder obtained by the method of this study is expected to be used as a value-added astaxanthin source.

Effects of Astaxanthin Preparation Form on the Efficiency of Egg Yolk Pigmentation in Laying Hens.

This study investigated the effects of the preparation form of astaxanthin on egg yolk pigmentation and egg quality in laying hens. The following four astaxanthin sources were prepared in this study: (1) dried cell powder of Paracoccus carotinifaciens (Panaferd-AX), (2) fine cell powder of P. carotinifaciens (Panaferd-P), (3) astaxanthin oil suspension, and (4) water-soluble astaxanthin powder. These astaxanthin preparations were added to the basal diet at a final concentration of 2 mg/kg and fed to White Leghorn laying hens for 14 days. Although the administration of these astaxanthin preparations did not largely affect egg quality (i.e., egg weight, yolk weight, albumen height, and Haugh unit), feeding significantly improved astaxanthin concentration and yolk color fan score. When water-soluble astaxanthin powder was fed, the yolk astaxanthin concentration and color fan score were most improved, followed by Panaferd-P. These results indicated that astaxanthin pulverization and water solubilization significantly improved its bioavailability in laying hens. Furthermore, although diets rich in (all-E)-astaxanthin were fed to the hens, approximately 30% of astaxanthin was present as the Z-isomers in the egg yolk. These findings may contribute to improving not only the egg quality but the nutritional value of hen eggs.

Improved Flesh Pigmentation of Rainbow Trout (Oncorhynchus mykiss) by Feeding Z-Isomer-Rich Astaxanthin Derived from Natural Origin.

The use of Paracoccus carotinifaciens-derived natural astaxanthin as an alternative to synthetic astaxanthin has attracted considerable attention from the aquaculture industry. Furthermore, to enhance the bioavailability of astaxanthin, its "Z-isomerization" has been actively studied in recent years. This study investigated the effects of feeding a diet containing astaxanthin rich in the all-E- or Z-isomers derived from P. carotinifaciens on the pigmentation and astaxanthin concentration in rainbow trout (Oncorhynchus mykiss) flesh. Z-Isomer-rich astaxanthin was prepared from the P. carotinifaciens-derived all-E-isomer by thermal treatment in fish oil, and the prepared all-E-isomer-rich astaxanthin diet (E-AST-D; total Z-isomerratio = 9.1%) and Z-isomer-rich astaxanthin diet (Z-AST-D; total Z-isomer ratio of astaxanthin = 56.6%) were fed to rainbow trout for 8 weeks. The feeding of Z-AST-D resulted in greater pigmentation and astaxanthin accumulation efficiency in the flesh than those fed E-AST-D. Specifically, when E-AST-D was fed to rainbow trout, the SalmoFan score and astaxanthin concentration of the flesh were 22.1±1.4 and 1.36±0.71 µg/g wet weight, respectively, whereas when Z-AST-D was fed, their values were 26.0±2.5 and 5.33±1.82 µg/g wet weight, respectively. These results suggest that P. carotinifaciens-derived astaxanthin Z- isomers prepared by thermal isomerization are more bioavailable to rainbow trout than the all-E-isomer.

Effects of Cyclic High Ambient Temperature on Muscle Imidazole Dipeptide Content in Broiler Chickens.

Imidazole dipeptides possess important bioregulatory properties in animals. This study aimed to evaluate the effect of high ambient temperature on muscle imidazole dipeptides (carnosine, anserine, and balenine) in broiler chickens. Sixteen 14-day-old male broiler chickens were divided into two groups, which were reared under thermoneutral (25 ± 1 °C) or cyclic high ambient temperature (35 ± 1 °C for 8 h/day) for 4 weeks. Chickens exposed to cyclic high ambient temperatures displayed lower skeletal muscle anserine and carnosine content than control chickens. Balenine could not be detected in the pectoral muscle of either group. The pectoral muscles of broiler chickens kept under cyclic high-temperature exhibited significantly lower mRNA expression of carnosine synthase 1, which synthesizes carnosine and anserine; but a significantly higher mRNA expression of carnosinase 2, which degrades carnosine and anserine. Our results suggest that heat exposure decreases pectoral imidazole dipeptide content in broiler chickens. This may be attributed to a lower expression of imidazole dipeptide-synthesizing genes, but higher levels of genes involved in their degradation.

Characteristics of LED light-induced geometrical isomerization and degradation of astaxanthin and improvement of the color value and crystallinity of astaxanthin utilizing the photoisomerization.

The effects of light-emitting diode (LED) irradiation characterized by different emission wavelengths on the E/Z-isomerization and degradation of astaxanthin were investigated. LED irradiation slightly promoted Z-isomerization of astaxanthin, whereas the all-E-isomerization was highly efficiently promoted at specific wavelengths, especially at 365 nm. Astaxanthin isomers did not degrade significantly when dissolved in ethanol and subjected to LED irradiation conditions for 300 min. However, significant degradation was achieved when ethyl acetate was used for dissolution, and the samples were irradiated at the wavelength of 405 nm. The addition of α-tocopherol suppressed the photodegradation of astaxanthin. LED irradiation significantly affected the physical properties of astaxanthin Z-isomers. Irradiation with 365, 405, and 470 nm LEDs enhanced the color value (redness) and crystallinity of the Z-isomers via an all-E-isomerization reaction. These findings can contribute to the development of technologies that can arbitrarily control the E/Z-isomer ratio and physical properties of astaxanthin.

Soft robotic shell with active thermal display.

Almost all robotic systems in use have hard shells, which is limiting in many ways their full potential of physical interaction with humans or their surrounding environment. Robots with soft-shell covers offer an alternative morphology which is more pleasant in both appearance and for haptic human interaction. A persisting challenge in such soft-shell robotic covers is the simultaneous realization of softness and heat-conducting properties. Such heat-conducting properties are important for enabling temperature-control of robotic covers in the range that is comfortable for human touch. The presented soft-shell robotic cover is composed of a linked two-layer structure: (1) The inner layer, with built-in pipes for water circulation, is soft and acts as a thermal-isolation layer between the cover and the robot structure, whereas (2) the outer layer, which can be patterned with a given desired texture and color, allows heat transfer from the circulating water of the inner part to the surface. Moreover, we demonstrate the ability to integrate our prototype cover with a humanoid robot equipped with capacitance sensors. This fabrication technique enables robotic cover possibilities, including tunable color, surface texture, and size, that are likely to have applications in a variety of robotic systems.

Evaluation and improvement of storage stability of astaxanthin isomers in oils and fats.

Astaxanthin Z-isomers potentially have greater bioavailability and biological activity than (all-E)-astaxanthin. However, the stability of the Z-isomers is lower than the all-E-isomer, which is a serious problem affecting its practical use. In this study, we investigated the impacts of different suspension media (oils and fats) and additives on astaxanthin isomer stability and identified suitable ones for astaxanthin stabilization. The evaluations showed that several vegetable oils and antioxidants significantly improved astaxanthin isomer stability, e.g., when soybean and sunflower oils were used as the suspension medium, astaxanthin isomers were hardly degraded; however the total Z-isomer ratio decreased from ~80% to ~50% during 6-week storage at 30 °C. Moreover, it was revealed that (9Z)-astaxanthin showed higher stability than the 13Z- and 15Z-isomers. Hence, to maintain astaxanthin concentration and the Z-isomer ratio over long periods, it is important to use suitable suspension mediums and antioxidants, and select a Z-isomerization method that increases (9Z)-astaxanthin ratio.

Z-Isomers of Astaxanthin Exhibit Greater Bioavailability and Tissue Accumulation Efficiency than the All-E-Isomer.

The purpose of the present study was to clarify the differences in the bioavailability and tissue accumulation efficiency between (all-E)- and (Z)-astaxanthin. Astaxanthin with a high proportion of the Z-isomer (especially rich in the 9Z- and 13Z-isomers) was prepared from (all-E)-astaxanthin by thermal treatment and solid-liquid separation. The all-E-isomer- or Z-isomer-rich diet was fed to male rats for 2 weeks. After the feeding period, blood and tissue samples were collected, and their astaxanthin levels were evaluated. The Z-isomer-rich astaxanthin diet resulted in higher levels of astaxanthin in blood and many tissues (in particular, skin, lung, prostate, and eye) compared to the all-E-isomer-rich diet. Moreover, the Z-isomer-rich diet enhanced the level of the 13Z-isomer in blood and tissues rather than that of the 9Z-isomer. These results strongly supported that astaxanthin Z-isomers have greater bioavailability and tissue accumulation efficiency than the all-E-isomer. Moreover, (13Z)-astaxanthin would have higher bioavailability and tissue accumulation than the other isomers.

Low mucosal-associated invariant T-cell number in peripheral blood of patients with immune thrombocytopenia and their response to prednisolone.

Mucosal-associated invariant T (MAIT) cells help protect against certain infections and are related to some autoimmune diseases. Immune thrombocytopenia (ITP) is a relatively rare hematological autoimmune disease associated with low platelet count. We designed a cross-sectional study wherein we examined peripheral blood samples of patients with ITP for the number of MAIT cells (CD3+TCR-Vα7.2+CD161+IL-18Rα+ lymphocytes) and their CD4/8 subsets (by flow cytometry) and levels of cytokines (by multiplex assays). The study cohort included 18 patients with ITP and 20 healthy controls (HCs). We first compared the number of MAIT cells between HCs and patients with ITP and then performed subgroup analysis in patients with ITP. The number of total MAIT cells in patients with ITP was significantly lower than that in HCs (p < 0.0001), and the CD4-CD8+ subset of MAIT cells showed the same trend. Moreover, patients with ITP refractory to prednisolone exhibited a significantly lower number of total MAIT and CD4-CD8+ MAIT cells than patients sensitive to prednisolone. The number of total MAIT and CD4-CD8+ MAIT cells was not correlated with the response to thrombopoietin receptor agonist treatment or with Helicobacter pylori infection. We found no relation between cytokine levels and response to prednisolone treatment, although the levels of IP-10 and RANTES showed a correlation with the number of total MAIT and CD4-CD8+ MAIT cells. In conclusion, total MAIT and CD4-CD8+ MAIT cells in peripheral blood were decreased in patients with ITP, correlating with their response to prednisolone.

TAK1 inhibition ameliorates survival from graft-versus-host disease in an allogeneic murine marrow transplantation model.

Acute graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in allogeneic hematopoietic cell transplantation (allo-HCT). Majority of the current immunosuppressive strategies targeting donor T cells to prevent or treat acute GVHD are only partially effective, and often require escalated immunosuppressive therapy. Recent studies have revealed that activation of antigen-presenting cells in the proinflammatory milieu is important for the priming and promotion of GVHD. This activation is mediated by innate immune signaling pathways, which therefore potentially represent new targets in addressing GVHD. Using gene expression analysis of peripheral monocytes from patients' post-allo-HCT, we detected an upregulation of TGF-ß-activated kinase 1 (TAK1), a key regulator of the toll-like receptor signaling pathway. 5Z-7-oxozeaenol, a selective inhibitor of TAK1, reduced proinflammatory cytokine production by activated monocytes under lipopolysaccharide stimulation and T cell proliferation in allogeneic-mixed leukocyte reactions with monocyte-derived dendritic cells. In an experimental mouse model of GVHD, 5Z-7-oxozeaenol administration after allo-HCT ameliorated GVHD severity and mortality, with significant reduction in serum TNFα, IL-1ß, and IL-12 levels. Our findings suggest that altering the activation status of innate immune cells by TAK1 inhibition may be a novel therapeutic approach for acute GVHD.

CBL mutation and MEFV single-nucleotide variant are important genetic predictors of tumor reduction in glucocorticoid-treated patients with chronic myelomonocytic leukemia.

Glucocorticoid (GC) therapy occasionally relieves tumor-related fever and promotes tumor reduction in patients with chronic myelomonocytic leukemia (CMML). A mutation analysis of 24 patients with CMML revealed the relationship of GC effectiveness, defined as a monocyte reduction of > 50% within 3 days of methylprednisolone administration, with the MEFV single-nucleotide variant (SNV) and CBL mutation. Lipopolysaccharide-stimulated monocytes harboring MEFV E148Q produced greater amounts of IL-1ß and TNF-α than did wild-type monocytes; this was effectively suppressed by GC. Primary CMML cells harboring the MEFV SNV and CBL mutation, and the myelomonocytic leukemia cell line GDM-1, harboring the CBL mutation, were both more significantly suppressed than non-mutated cells following GC treatment in the presence of GM-CSF. A loss-of-function CBL mutation prolonged STAT5 phosphorylation after GM-CSF stimulation, which was rapidly terminated in both patient samples and GDM-1 cells. In conclusion, GC therapy effectively treats CMML cells harboring the MEFV SNV and CBL mutation by reducing inflammatory cytokine production and terminating prolonged STAT5 phosphorylation in the GM-CSF signaling pathway.

Two Cases of Liver Abscesses Derived from Dental Disease in Patients with Alcoholic Chronic Pancreatitis.

Among the etiologies of pyogenic liver abscess (PLA), bacterial spread from the biliary tract or portal flow is the major cause, while the onset of PLA due to arterial bacterial transmission is rare. We herein report two cases of PLA thought to be caused by arterial transmission from dental disease. In both cases, there was benign biliary stricture as a result of alcoholic chronic pancreatitis, although normal oral flora was detected as the causative bacteria and oral hygiene was poor in both patients. We presumed that the origin of PLA was dental disease and successfully treated the patients with percutaneous drainage, antibiotics and dental procedures.

Elevated total iron-binding capacity as a predictor of response to deferasirox therapy in the setting of chronic iron overload.

It is difficult to predict the efficacy of deferasirox (DFX) as its pharmacokinetics varies among patients. The area under the curve (AUC) is reportedly useful for determining adequate DFX dosage; however, serum concentration measurements are often challenging. Effective DFX dosage is thus defined by assessing the efficacy of this agent in clinical practice. To analyze a predictive response marker to DFX therapy for use in adjusting the effective dosage during the early treatment phase, we retrospectively evaluated 39 DFX-treated patients. We defined response as a >40 % decrease in serum ferritin concentration from the pretreatment level. A maximum elevation of the total iron-binding capacity (TIBC) correlated with response in a multivariate analysis of iron metabolic markers (R (2) = 0.37, p < 0.001). A receiver operating characteristic curve analysis revealed that TIBC elevation had an AUC of 0.85 (p < 0.001) and the optimal cut-off value of TIBC elevation was 150 µg/dl. TIBC elevation of >150 µg/dl is a favorable predictor of effective ferritin reduction in DFX therapy (hazard ratio 29.6, 95 % confidence interval 4.8-183.6; p < 0.001). DFX therapy with TIBC monitoring may enable the determination of the minimum effective DFX dosage.